我们之前已经证明了THY1 (CD90)是鼻咽癌 (NPC) 的一个肿瘤抑制因子，其下调和表达丧失与肿瘤转移有关，然而导致这些效应的机制仍然不清楚。在本研究中，我们展示了通过NPC细胞系中粘附连接形成的方式，THY1可以抑制肿瘤侵袭，并且THY1的敲低会破坏这种细胞间粘附表型。机制上，当THY1被固定表达时，SRC家族激酶 (SFK) 成员SRC的活性和经典Wnt信号显著降低。其他研究表明，NPC细胞中高水平的SRC活性与EMT和恶性预后有关。我们假设通过抑制SRC，THY1可以抑制NPC的肿瘤侵袭。通过靶向SRC基因沉默，我们发现体外NPC细胞侵袭显著降低，并且粘附连接得到恢复。通过蛋白组学分析，我们发现血小板源性生长因子受体β (PDGF-Rβ) 和非受体型蛋白酪氨酸磷酸酶22型 (PTPN22) 是THY1的新的潜在结合伴侣，随后通过共免疫沉淀 (co-IP) 分析进行验证。PDGF-Rβ的配体 (PDGF-BB) 可以高度诱导SRC的活性和NPC细胞侵袭，这可以几乎完全被THY1表达抑制。另一方面，PTPN22 siRNA可以增强SRC的活性和细胞侵袭，并且也会破坏THY1表达的NPC细胞中的粘附连接；当PTPN22表达降低时，原始的THY1诱导表型被恢复。总的来说，我们的结果表明，PTPN22对于THY1抑制细胞侵袭和SRC活性，维持紧密的粘附连接，以及预防NPC转移至关重要。这些结果表明，PDGF-Rβ和SRC可以用作抑制NPC转移的药物靶点。事实上，我们使用SRC抑制剂KX2-391进行的体内实验清晰地表明通过抑制SRC信号可以预防NPC的转移，表明靶向SRC可以是控制NPC进展的一种有前途的方法。

We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that tumor invasion could be suppressed by THY1 via adherens junction formation in a few NPC cell lines, and knockdown of THY1 would disrupt this cell-cell adhesion phenotype. Mechanistically, the activity of the SRC family kinase (SFK) member, SRC, and canonical Wnt signaling were dramatically reduced when THY1 was constitutively expressed. Previous studies by others have found that high levels of SRC activity in NPCs are associated with EMT and a poor prognosis. We hypothesized that THY1 can suppress tumor invasion in NPC via inhibition of SRC. By gene silencing of SRC, we found that the in vitro NPC cell invasion was significantly reduced and adherens junctions were restored. Through proteomic analysis, we identified that platelet-derived growth factor receptor β (PDGF-Rβ) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) are novel and potential binding partners of THY1, which were subsequently verified by co-immunoprecipitation (co-IP) analysis. The ligand of PDGF-Rβ (PDGF-BB) could highly induce SRC activation and NPC cell invasion, which could be almost completely suppressed by THY1 expression. On the other hand, the PTPN22 siRNA could enhance both the SRC activities and the cell invasion and could also disrupt the adherens junctions in the THY1-expressing NPC cells; the original THY1-induced phenotypes were reverted when the PTPN22 expression was reduced. Together, our results identified that PTPN22 is essential for THY1 to suppress cell invasion and SRC activity, maintain tight adherens junctions, and prevent NPC metastasis. These results suggested that PDGF-Rβ and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression.